This invention relates to novel steroids and more particularly to androsterone derivatives useful as anti-cancer, anti-obesity, anti-diabetic and hypolipidemic agents.
Dehydroepiandrosterone (DHEA) and DHEA-sulfate are major adrenal secretory products in humans. The plasma concentration of DHEA-sulfate, which next to cholesterol, is the most abundant steroid in humans, undergoes the most marked age-related decline of any known steroid.
Although DHEA-sulfate is the main precursor of placental estrogen and may be converted into active androgens in peripheral tissue, there is no obvious biological role for either DHEA or DHEA-sulfate in the normal individual. Several retrospective and prospective studies suggest that women with sub-normal levels of these steroids may be predisposed to develop breast cancer. For example, see Brownsey, et al., "Plasma dehydroepiandrosterone sulfate levels in patients with benign and malignant breast disease," Eur. J. Cancer, 8, 131-137 (1972); Bulbrook, et al., "Relation between urinary androgen and corticoid excretion and subsequent breast cancer," Lancet, 2, 395-398 (1971); Rose, et al., "Plasma dehydroepiandrosterone sulfate, androstenedione and cortisol, and urinary free cortisol excretion in breast cancer, "Eur. J. Cancer, 13, 43-47 (1977); Wang, et al., "Studies of the sulfate esters of dehydroepiandorsterone and androsterone in the blood of women with breast cancer," Eur. J. Cancer, 10, 477-482 (1974); and Zumoff, et al., "Abnormal 24-hr mean Plasma concentrations of dehydroisoandrosterone and dehydroisoandrosterone sulfate in women with primary operable breast cancer," Cancer Research, 41, 3360-3363, September, 1981.
It has also been established that DHEA is a potent non-competitive inhibitor of mammalian glucose-6-phosphate dehydrogenase (G6PDH). For example, see Oertel, et al., "The effects of steroids on glucose-6-phosphate dehydrogenase," J. Steroid Biochem., 3, 493-496 (1972) and Marks, et al., "Inhibition of mammalian glucose-6-phosphate dehydrogenase by steroids," Proc. Nat'l Acad. Sci, USA, 46, 477-452 (1960). Moreover, Yen, et al., "Prevention of obesity in A.sup.vy /a mice by dehydroepiandrosterone," Lipids, 12, 409-413 (1977), reported that long-term administration of DHEA to VY-A.sup.vy /a mice prevented the development of obesity without suppressing appetite.
Furthermore, it is also known that the long-term treatment of C3H mice with DHEA, in addition to reducing weight gain without suppressing appetite, markedly inhibits spontaneous breast cancer development and may delay the rate of aging. It has been observed that DHEA antagonizes the capacity of the tumor promoter, 12-0-tetradecanoylphorbol-13-acetate, to stimulate .sup.3 H-thymidine incorporation in mouse epidermis and in a cultured rat kidney epithelial cell line. See, Schwartz, "Inhibition of spontaneous breast cancer formation in female C3H-A.sup.vy /a mice by long-term treatment with dehydroepiandrosterone, Cancer Res., 39, 1129-1132 (1979); and Schwartz, et al., "Dehydroepiandrosterone: an anti-obesity and anti-carcinogenic agent," Nut. Cancer 3, 46-53 (1981).
Ben-David, et al., "Anti-hypercholesterolemic effect of dehydroepiandrosterone in rats," Proc. Soc. Expt. Biol. Med., 125, 1136-1140 (1967) have observed that DHEA treatment has an anti-hypercholesterolemic effect in mice, while Coleman, et al. (Diabetes 31, 830, 1982) report that administration of DHEA produces a marked hypoglycemic effect in C57BL/KsJ-db/db mice. The latter authors suggest that the therapeutic effect of DHEA might result from its metabolism to estrogens.
It is further known that DHEA and 16.alpha.-bromoepiandrosterone are inhibitors of Epstein-Barr virus-induced transformation of human lymphocytes and that 16.alpha.-bromoepiandrosterone is a more potent inhibitor of mammalian G6PDH than DHEA. See, Schwartz, et al. Carcinogensis, Vol. 2 No. 7, 683-686 (1981).
While DHEA has been found effective in the afore-described manners, there is however, evidence of an estrogenic effect after prolonged administration. DHEA is not an estrogen per se but is well known to be convertible into estrogens. In addition, the therapeutic dose of DHEA is rather high. It would therefore be highly desirable to provide steroids, which while having the same afore-described advantage of DHEA are more potent and do not produce an estrogenic effect.
Besides DHEA, other steroids are known in the art.
Great Britain Patent No. 989,503 to Burn, et al. discloses 6,16.beta.-dimethyl-3.beta.hydroxyandrost-5-en-17-ones. These compounds are disclosed to be useful as possessing pituitary inhibiting action.
U.S. Pat. No. 2,833,793 to Dodson, et al. discloses 1.beta.,3.beta.-dihydroxy-5-androsten-17-one as an androgenic and anabolic agent.
U.S. Pat. No. 2,911,418 to Johns, et al. discloses 16.alpha.-chloro-3.beta.-hydroxyandrost-5-en-17-one and 3.beta.-hydroxy-16.alpha.-iodoandrost-5-en-17-one as an anti-androgen.
Goldkamp, et al. in U.S. Pat. No. 3,148,198 disclose that 16.alpha.,16.beta.-difluoro-3.beta.-hydroxyandrost-5-en-17-one possess androgenic properties.
French Application No. FR-A 2,317,934 discloses the following compounds:
3.beta.-hydroxy-16{-methylandrost-5-en-17-one PA0 3.beta.-hydroxy-16{-ethylandrost-5-en-17-one PA0 3.beta.-hydroxy-16{-isopropylandrost-5-en-17-one PA0 (a) 3.beta.-iodo-.DELTA..sup.5 -6-methyl-17-oxoandrostene PA0 (b) 3.beta.-chloro-.DELTA..sup.5 -6-methyl-17-oxoandrostene PA0 (c) 3.beta.-hydroxy-.DELTA..sup.5 -6-methyl-17-oxoandrostene PA0 3.beta.-hydroxy-16.alpha.-bromo-5.alpha.-androstan-17-one PA0 3.beta.-hydroxy-16.alpha.-chloro-5.alpha.-androstan-17-one PA0 3.beta.-hydroxy-16.alpha.-fluoro-5.alpha.-androstan-17-one PA0 3.beta.-hydroxy-16.alpha.-iodo-5.alpha.-androstan-17-one PA0 3.beta.-hydroxy-16.alpha.-bromoandrost-5-ene-17-one PA0 16.beta.bromoandrostan-17-one PA0 3.beta.-hydroxy-16.alpha.-chloro-5.alpha.-androstan-17-one, PA0 3.beta.-hydroxy-16.alpha.-fluoro-5.alpha.-androstan-17-one, PA0 3.beta.-hydroxy-16.alpha.-bromo-5.alpha.-androstan-17-one , PA0 3.beta.-hydroxy-16.alpha.-iodo-5.alpha.-androstan-17-one. PA0 3.beta.-hydroxy-5.alpha.-androstan-17-one PA0 3.beta.-hydroxy-5.beta.-androstan-17-one PA0 3.alpha.-hydroxy-5.alpha.-androstan-17-one PA0 11.beta.-hydroxy-5.alpha.-androstan-17-one PA0 3.alpha.-hydroxy-4.alpha.-methyl-5.alpha.androstan-17-one PA0 3.alpha.-hydroxy-7.alpha.-methyl-5.alpha.androstan-17-one PA0 3.beta.-hydroxy-7.alpha.-methyl-5.beta.androstan-17-one PA0 3.beta.-hydroxy-16.alpha.-bromo-5.alpha.androstan-17-one PA0 3.beta.-chloro-5.alpha.-androstan-17-one.
U.S. Pat. No. 3,976,691 discloses the following compounds: ##STR2##
U.S. Pat. No. 3,471,480 to Fritsch, et al. discloses the following compounds which are useful as progestational agents:
Hanson, et al. in Perkin Transactions I, 1977, pp. 499-501, disclose 3.beta.,4.beta.-dihydroxyandrost-5-en-17-one. No utility is disclosed.
Chemical Abstract 89:105866b discloses that 3.beta.-hydroxy-5.beta.-androstan-17-one can be hydroxylated in the 15.beta.-position. Furthermore, said reference teaches that hydroxylation of 3.beta.-hydroxy-5.alpha.androsten-17-one gave both the 7.alpha. and 7.beta.-hydroxyisoandrosterones.
Numazawa, et al. in Steroids, 32, 519-527 disclose 3.beta.,16.alpha.-dihydroxyandrost-5-en-17-one. No utility is disclosed.
DE-A- 2,035,738 discloses 7.alpha.-Methyl-3.beta.-hydroxy-5-androsten-17-one and 6,7.alpha.-dimethyl-3.beta.-hydroxy-5-androsten-17-one.
DE-A2 705917 discloses 3.beta.,16.beta.-dihydroxy-5-androsten-17-one.
The Annual Report of the Fels Research Institute, pp. 32-33, (1979-1980) discloses the following compounds as having tumor-preventive, anti-obesity and anti-aging qualities:
Abou-Gharbia, et al. in Journal of Pharmaceutical Sciences, 70, 1154-1156 (1981) disclose the syntheses of:
Pashko, et al. in Carcinogenesis, 2, 717-721 (1981) disclose that 16.alpha.-Br-epiandrosterone is more active than DHEA in inhibiting G6PDH and in reducing the rate of [.sup.3 H] thymidine incorporation into mouse breast epithilum and epidermis. The authors suggest that this compound may be useful in suppressing breast cancer development.
Neef, et al. in Journal of Org. Chem., 43, 4679-4680 disclose the syntheses of 3.beta.-hydroxy-16.alpha.-methyl-5-androsten-17-one and 3.beta.-hydroxy-16.beta.-methyl-5-androsten-17-one. androsten-17-one.
Robinson, et al. in Journal of Org. Chem., 28, 975-980 (1963) disclose the synthesis of 3.beta.-hydroxy-16.alpha.,16.beta.-difluoro-5-androsten-17-one.
Rarnier, et al. in Biochemistry, 9, 2233-2243 (1970) tested the inhibitory activity of the following steroids on NADP and NAD linked activity of glucose 6-phosphate dehydrogenase:
Gordon, et al. in Cancer Research 46, 3389-3395 (1986) disclose that DHEA, 16.alpha.-bromoepiandrosterone, epiandrosterone, 3.beta.-hydroxy-5.alpha.-pregnan-20-one, 5.alpha.-androstan-17-one and 5.alpha.-androstan-3.beta.,16.alpha.-diol-17-one are inhibitors of glucose 6-phosphate dehydrogenase. Furthermore, said reference discloses that testosterone, 17.beta.-Estradiol, 5-androstene-3.beta.,17.beta.diol, dehydroepiandrosterone-3-sulfate and 5.alpha.-androstan-17.beta.-ol are noninhibitors of glucose-6-phosphate dehydrogenase. The reference suggests that there is a general correlation between the structure requirements for blocking differentiation to adipocytes and inhibiting glucose-6-phosphate dehydrogenase.
Julian, et al. in JACS, 70, 3872-3876 (1948) discloses the preparation of 16-dimethylaminomethyldehydroisoandrosterone.
Peat in U.S. Pat. No. 4,628,052 discloses compositions containing the following compounds as the active ingredient: ##STR3## wherein R.sub.1 is O or OH and R.sub.2 is O, or OH; and which may contain one double bond in ring A and/or B or tocopherol.
The compounds are alleged to be useful in treating rheumatoid arthritis, osteoarthritis and arthritis associated with psoriasis and with lupus and other auto-immune diseases and also for treating non-specific joint pain associated with stress.